Toxic and antimitotic properties of a series of colchicine derivatives

Abstract

Colchicine and its natural analog colchamine possess pronounced stathmokinetic properties, but only colchamine, which has a lower toxicity but a narrow breadth of therapeutic action, is used in oncology. Our task was to find substances with lower toxicity and retained mitosis-inhibiting activity among new analogs of these alkaloids.It is known that the introduction of amino compounds into the tropolone ring of colchicine (1) and colchamine (9) leads to a lowering of toxicity. We obtained the following derivatives: amino-(2), monoethanolamino-(3), mercaptoethylamino- (5), diethylamino-(6), chloroethylamino- (7), and dichloroethylaminocolchicine (8) and monoethanolaminocolchicine derivatives (10). The acute toxicities and mitotic indices (MIs) of these substances were determined on crypts of the intestines of mice of the C57B1/6 line. Acute toxicities were determined by the intraperitoneal (i/p) administration of the substances under study to mice weighing 20-22 g, and MIs also by the i/p administration of the preparations in doses corresponding to 1/2 LDt6" Animals were decapitated after 30 and 60 min and each hour in the course of a day, and 1 cm of the duodenum (taken 1 cm below the pyloric end of the stomach) was used for histological investigations. This section of the duodenum was fixed in Bowen's mixture and was then flooded with paraffin, and histological sections were prepared and were stained with hematoxylin-eosin. Under the microscope, the number of cells in a crypt and the number of dividing cells were counted, and the MI and mitotic activity were calculated. On average, not less than three animals were used for each point.As can be seen from Table 1, replacement of the methoxy group of the tropolone ring by various amino compounds lowered the toxicity by a factor of more than 10. The formation of hydrochlorides (4, 6) increased water solubility but doubled toxicity. An increase in the number of ethanolamine groups had practically no effect on the toxic properties. The chloroethyl-

Investigation of Mechanism Activity of Antitumor and Radiosensitizing Activity of Preparations К-26 and K-26w

“…At studying, mitotic index (MI) epithelial crypt on bowels [7], in various terms after introduction К-26 in comparison with initial colchicine it is shown, that the maximum delay mitotic divisions observed at introduction colchicine (35.73±0.26%) after 6 hours, and for К-26 MI were more low-about 23%, however in comparison with the control on 19% above.…”

“…After decapitation animals, took away 1sm of a duodenal gut for histological research and fixed in mix Bowen. Mitotic index (MI) and mitotic activity (MA) defined a standard histology method [7].…”